What are the two goals sought in treatment of asthma?
Which phase of mast cell activation do they correspond to?
Bronchodilators to reverse the initial bronchoconstriction (mast cell degranulation)
Anti-inflammatories to counter the late-phase obstruction (delayed mast cell mediator release)
What is the mechanism of action and indication for Cromolyn sodium?
What are its side effects, and how popular is it?
Cromolyn sodium stabilizes mast cells through an unknown mechanism, and is used for chronic control of asthma.
It is inhaled, has few side effects, yet isn't available in the US.
What is its mechanism of action?
What are its indications?
Inhibits IgE receptors (FceRI/II) to inhibit mast cells and other inflammatory processes.
For very severe asthma, with concomitant allergic rhinitis.
How is it administered?
What are its adverse effects?
Subcutaneously, once every 2-4 weeks.
Same as any mAb: Injection site reaction, anaphylaxis.
What are three classes of bronchodilators?
What do they accomplish?
Which is the treatment of choice for asthma?
Beta-2 agonists, methylxanthines, and anticholinergics.
Relax airway smooth muscle to cause bronchodilation (or prevent bronchoconstriction).
Beta-agonists are the drug of choice.
Distinguish between albuterol, salmeterol, and formoterol.
Albuterol is a short-acting beta-agonists (SABA), used as a rescue inhaler.
Salmeterol & formoterol are long-acting beta-agonists (LABAs), used for management of chronic asthma.
Compare and contrast the pharmacokinetics of SABAs and LABAs.
Why might salmeterol, for example, have a comparably long half-life?
SABAs act quickly and last 3-6 hours.
LABAs take longer to cause effect (inappropriate for rescue), and last for at least 12 hours.
Salmeterol's aliphatic side-chain binds a beta-2 receptor exosite for binding stability.
What is the pathway activated by beta-2 agonists in airway smooth muscle?
How is this helpful in fighting Asthma & COPD?
Beta-2 receptor is a Gs, activates AC/cAMP/PKA to reduce intracellular calcium.
This causes relaxation of the smooth muscle cell, reducing bronchial tone.
Asides from bronchodilation, what beneficial effects to beta-2 agonists have?
Prevent mediator release from mast cells
Prevent bronchial mucosal edema
Enhance mucociliary clearance
Reduce reflex bronchoconstriction (?)
What side effects can be associated with beta-2 agonists?
Why is this, and how can they be reduced?
Muscle tremor, tachycardia, hypokalemia, restlessness, hypoxemia. Also, tolerance with chronic use.
Mostly due to extrapulmonary beta receptor activation. Give drug as an inhalant.
Why is it meaningful to ask a patient how often they use their rescue inhaler?
How frequently should a LABA be used?
Increased SABA usage indicates the need for anti-inflammatory therapy.
LABAs are generally used twice daily (~12hr duration)
Why aren't LABAs considered first-line treatments for asthma?
They are too slow to be used for immediate relief, and may be associated with higher mortality (especially in children)
What role may pharmacogenetics play in the context of asthma treatment?
There are multiple polymorphisms of the beta-2 receptor. Some may correspond to more adverse effect with SABA/LABA use.
What class of drug does it belong to?
What are its mechanisms of action?
It is a methylxanthine (like caffeine)
Weak, nonspecific PDE inhibition and adenosine receptor antagonism, which both promote bronchodilation.
How is it administered?
What are its side effects?
Broad side effects (headache, palpitations, dizziness, nausea, hypotension), some related to the adenosine receptor antagonism (seizures, arrhythmias). Less popular than beta-agonists.
Name a couple of examples and distinguish them.
What effects of acetylcholine do they block?
Ipratropium & tiotropium (short and long-lasting, respectively)
Block ACh-mediated construction (via M3-PLC pathway) and mucus secretion.
How is ipratropium administered?
Describe its pharmacokinetics.
What are its side effects?
Effect onset over 30-90min, effects last 4-6 hours.
Typical of muscarinic blockade: Dry mouth, constipation, cycloplegia, dyspepsia, cognitive impairment (hot as a hare, red as a beet, blind as a bat, dry as a bone, mad as a hatter)
What drugs could be added to beta-agonists?
Ipratropium has additive effect, mix them when beta-agonists aren't adequate alone.
Inhaled corticosteroids have synergistic effect with beta-agonists, they are mixed often.
How do steroids alleviate asthma?
How don't they?
Actviation of the GC receptor causes suppression of inflammatory elements (like NF-kB) via histone deacetylase-2 (HDAC2).
Also downregulate inflammatory cells, mediators, and mucus, as well as increasing beta-2 receptors.
Steroids have no effect on smooth muscle contraction/dilation.
Recall why beta-agonists and inhaled corticosteroids go so well together.
Name a couple of real world combinations.
Both upregulate the expression of the other's receptor.
Fluticasone + Salmeterol = Advair
Budesonide + Formoterol = Symbicort
When are oral steroids indicated? Which ones?
IV? Which ones?
For severe asthma (step 6), in short courses. Prednisone/prednisolone.
For severe acute asthma. Hydrocortisone ("rapid" onset)
What side effects are associated with steroids in general?
With inhaled steroids?
ACTH/HPA suppression, which can be catastrophic.
Dermal thinning, cataracts*, osteroporosis*, vocal cord atrophy.
What are the indications and frequency of use for ICS?
First-line for patients who use a beta-agonist more than twice weekly. (step 2)
Used twice daily.
How do leukotriene inhibitors block asthma?
What are some examples?
Why are they useful against aspirin-induced asthma?
Block the effects of LTs: Bronchoconstriction, edema, mucus, eosinophilic inflammation.
Zileuton (blocks 5-LO), Montelukast/zafirlukast (antagonize cys-LT1 receptor).
Aspirin-induced asthma results from arachidonate shunting to the leukotriene pathway. These block it.
How are leukotriene antagonists administered?
What are their indications?
What are their adverse effects?
For mild-moderate asthma as an add-on for patients in which ICS have failed.
Rare hepatic dysfunction.
Review the steps of asthma treatment. Order the following indications from least to most severe usage.
High dose ICS
Low dose ICS
What are the first-line treatments for COPD?
Anticholinergics or beta-agonists.
Why do anticholinergics have greater application in COPD than asthma?
The bronchodilatory effects are greater in COPD, because of the structural (rather than smooth muscle mediated) narrowing.
Compare the use of ICS in COPD and Asthma.
What about oral steroids?
ICS are first-line for asthma, but not for ICS. ICS relieves symptoms of COPD, but do not improve mortality.
Oral steroids reserved for serious asthma, while COPD is generally unresponsive to oral steroids.
What drugs, besides anticholinergics and ICS, are used to treat COPD? Give examples for each class.
Mucolytic (N-Ac to break disulfide bonds)
PDE4 inhibitors (Roflumilast)